scholarly journals p53 mutations are associated with histologic transformation of follicular lymphoma

Blood ◽  
1993 ◽  
Vol 82 (8) ◽  
pp. 2289-2295 ◽  
Author(s):  
F Lo Coco ◽  
G Gaidano ◽  
DC Louie ◽  
K Offit ◽  
RS Chaganti ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Direct Sequencing ◽  
Gene Mutations ◽  
P53 Gene ◽  
Single Strand Conformation Polymorphism ◽  
Low Grade ◽  
Diffuse Type ◽  
P53 Mutations ◽  
Clinical Progression ◽  
Hodgkin's Lymphomas

Abstract The majority of low-grade non-Hodgkin's lymphomas (NHL) undergo clinical progression toward intermediate- and high-grade lymphomas. This progression is often associated with histologic transformation from follicular to diffuse-type NHL. The pathogenetic mechanisms underlying this evolution are presently unknown. In this study, we have analyzed the role in NHL progression of relevant genetic lesions affecting proto-oncogenes and tumor suppressor genes. Sequential biopsies from 21 patients with clinical progression with (5 cases) or without (16 cases) evidence of histologic transformation were analyzed for karyotypic changes, c-myc rearrangements and deletions affecting 6q27 by Southern blot analysis, and p53 mutations by single-strand conformation polymorphism (SSCP) analysis coupled with direct sequencing of polymerase chain reaction-amplified products. No novel cytogenetic aberration was detected in association with progression, and all samples analyzed displayed a normal c-myc gene. Mutations of the p53 gene were detected in 4 of 5 cases displaying histologic transformation from follicular to diffuse-type NHL and in none of the 16 cases displaying clinical progression in the absence of histologic transformation. In 1 of these positive cases, the same mutation was also present in the pretransformation biopsy, correlating with the presence of diffuse-type areas within a predominant follicular pattern. In 1 of these cases, a deletion of 6q27 was also detected in the posttransformation biopsy along with a p53 mutation. These findings indicate that p53 mutations are associated with and may be responsible for histologic transformation of follicular lymphoma.

scholarly journals p53 mutations are associated with histologic transformation of follicular lymphoma

Blood ◽  
1993 ◽  
Vol 82 (8) ◽  
pp. 2289-2295 ◽  
Author(s):  
F Lo Coco ◽  
G Gaidano ◽  
DC Louie ◽  
K Offit ◽  
RS Chaganti ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Direct Sequencing ◽  
Gene Mutations ◽  
P53 Gene ◽  
Single Strand Conformation Polymorphism ◽  
Low Grade ◽  
Diffuse Type ◽  
P53 Mutations ◽  
Clinical Progression ◽  
Hodgkin's Lymphomas

The majority of low-grade non-Hodgkin's lymphomas (NHL) undergo clinical progression toward intermediate- and high-grade lymphomas. This progression is often associated with histologic transformation from follicular to diffuse-type NHL. The pathogenetic mechanisms underlying this evolution are presently unknown. In this study, we have analyzed the role in NHL progression of relevant genetic lesions affecting proto-oncogenes and tumor suppressor genes. Sequential biopsies from 21 patients with clinical progression with (5 cases) or without (16 cases) evidence of histologic transformation were analyzed for karyotypic changes, c-myc rearrangements and deletions affecting 6q27 by Southern blot analysis, and p53 mutations by single-strand conformation polymorphism (SSCP) analysis coupled with direct sequencing of polymerase chain reaction-amplified products. No novel cytogenetic aberration was detected in association with progression, and all samples analyzed displayed a normal c-myc gene. Mutations of the p53 gene were detected in 4 of 5 cases displaying histologic transformation from follicular to diffuse-type NHL and in none of the 16 cases displaying clinical progression in the absence of histologic transformation. In 1 of these positive cases, the same mutation was also present in the pretransformation biopsy, correlating with the presence of diffuse-type areas within a predominant follicular pattern. In 1 of these cases, a deletion of 6q27 was also detected in the posttransformation biopsy along with a p53 mutation. These findings indicate that p53 mutations are associated with and may be responsible for histologic transformation of follicular lymphoma.

scholarly journals The expression of p53 protein in non-Hodgkin's lymphomas is not always dependent on p53 gene mutations

Blood ◽  
1993 ◽  
Vol 82 (10) ◽  
pp. 3151-3156 ◽  
Author(s):  
R Villuendas ◽  
MA Piris ◽  
P Algara ◽  
M Sanchez-Beato ◽  
L Sanchez-Verde ◽  
...  
Keyword(s):  
P53 Protein ◽  
Point Mutations ◽  
Gene Mutations ◽  
P53 Gene ◽  
Burkitt’S Lymphoma ◽  
Burkitt's Lymphoma ◽  
High Grade ◽  
P53 Mutations ◽  
P53 Gene Mutations ◽  
Hodgkin's Lymphomas

p53 overexpression has been found to be a fairly common feature in high grade lymphomas in the majority of tumoral cells. The results vary from series to series, from 25% to 33% of cases. To assess whether immunohistochemical positivity for p53 correlated with the presence of structural gene abnormalities, DNA from 16 non-Hodgkin's lymphomas with high and low p53 values was amplified and sequenced to determine the existence of point mutations in the highly conserved regions of the p53 gene. In the group of 8 cases containing high levels of protein, 3 cases showed missense point mutations at the codons mapping between exons 5 through 8. Of the 8 cases of tumors containing undetectable or low levels of p53 protein, 1 case presented a nonsense point mutation giving a stop codon. No missense mutations were detected in this group. The finding of p53 mutations in 4 of 16 cases confirms the presence of p53 gene mutations in high grade lymphomas distributed over different histologic groups. These include Burkitt's lymphoma, together with centroblastic, immunoblastic, and large cell lymphoma of mucosa origin. Nevertheless, the absence of mutations in 5 of the 8 cases that overexpressed p53 suggests that the nuclear or cytoplasmic stabilization of p53 protein could also depend on other factors. The absence of detectable levels of p53 protein cannot discount the existence of p53 mutations, as is shown by a case of Burkitt's lymphoma in which a nonsense mutation was detected. The impact of this range of p53 alterations on clinical course and treatment response of the patients deserves to be explored, in an attempt to differentiate the specific consequences of each one.

scholarly journals p53 gene mutations in multiple myeloma are associated with advanced forms of malignancy

Blood ◽  
1993 ◽  
Vol 81 (1) ◽  
pp. 128-135 ◽  
Author(s):  
A Neri ◽  
L Baldini ◽  
D Trecca ◽  
L Cro ◽  
E Polli ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Direct Sequencing ◽  
Point Mutations ◽  
Gene Mutations ◽  
P53 Gene ◽  
Single Strand Conformation Polymorphism ◽  
P53 Mutation ◽  
Late Event ◽  
Multistep Process ◽  
P53 Gene Mutations

Abstract The frequency and type of p53 gene mutations was investigated in a series of 52 cases of multiple myeloma (MM) representative of the different clinical phases and forms of the disease (indolent, 12 cases; chronic, 24 cases; acute/leukemic, 16 cases). DNAs were analyzed for p53 gene mutations in exons 5 to 9 by polymerase chain reaction (PCR), single-strand conformation polymorphism (SSCP), and direct sequencing of PCR-amplified fragments. Point mutations were detected in 7 of 52 patients (13%) (5 at exon 8; 1 at exon 6; 1 at exon 7), and were specifically associated with the more advanced and clinically aggressive acute/leukemic forms of MM (7 of 16 [43%].) Three of the mutated cases had been evaluated at clinical presentation in earlier phases of the disease (indolent or chronic) and were found to be negative for p53 mutation. Moreover, three patients with p53 mutation had not received chemotherapy at the time of investigation. These results support the notion that the development of MM is a multistep process and suggest that alterations in the p53 gene may represent an important late event in MM tumor progression.

scholarly journals p53 gene mutations in multiple myeloma are associated with advanced forms of malignancy

Blood ◽  
1993 ◽  
Vol 81 (1) ◽  
pp. 128-135 ◽  
Author(s):  
A Neri ◽  
L Baldini ◽  
D Trecca ◽  
L Cro ◽  
E Polli ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Direct Sequencing ◽  
Point Mutations ◽  
Gene Mutations ◽  
P53 Gene ◽  
Single Strand Conformation Polymorphism ◽  
P53 Mutation ◽  
Late Event ◽  
Multistep Process ◽  
P53 Gene Mutations

The frequency and type of p53 gene mutations was investigated in a series of 52 cases of multiple myeloma (MM) representative of the different clinical phases and forms of the disease (indolent, 12 cases; chronic, 24 cases; acute/leukemic, 16 cases). DNAs were analyzed for p53 gene mutations in exons 5 to 9 by polymerase chain reaction (PCR), single-strand conformation polymorphism (SSCP), and direct sequencing of PCR-amplified fragments. Point mutations were detected in 7 of 52 patients (13%) (5 at exon 8; 1 at exon 6; 1 at exon 7), and were specifically associated with the more advanced and clinically aggressive acute/leukemic forms of MM (7 of 16 [43%].) Three of the mutated cases had been evaluated at clinical presentation in earlier phases of the disease (indolent or chronic) and were found to be negative for p53 mutation. Moreover, three patients with p53 mutation had not received chemotherapy at the time of investigation. These results support the notion that the development of MM is a multistep process and suggest that alterations in the p53 gene may represent an important late event in MM tumor progression.

scholarly journals The expression of p53 protein in non-Hodgkin's lymphomas is not always dependent on p53 gene mutations

Blood ◽  
1993 ◽  
Vol 82 (10) ◽  
pp. 3151-3156 ◽  
Author(s):  
R Villuendas ◽  
MA Piris ◽  
P Algara ◽  
M Sanchez-Beato ◽  
L Sanchez-Verde ◽  
...  
Keyword(s):  
P53 Protein ◽  
Point Mutations ◽  
Gene Mutations ◽  
P53 Gene ◽  
Burkitt’S Lymphoma ◽  
Burkitt's Lymphoma ◽  
High Grade ◽  
P53 Mutations ◽  
P53 Gene Mutations ◽  
Hodgkin's Lymphomas

Abstract p53 overexpression has been found to be a fairly common feature in high grade lymphomas in the majority of tumoral cells. The results vary from series to series, from 25% to 33% of cases. To assess whether immunohistochemical positivity for p53 correlated with the presence of structural gene abnormalities, DNA from 16 non-Hodgkin's lymphomas with high and low p53 values was amplified and sequenced to determine the existence of point mutations in the highly conserved regions of the p53 gene. In the group of 8 cases containing high levels of protein, 3 cases showed missense point mutations at the codons mapping between exons 5 through 8. Of the 8 cases of tumors containing undetectable or low levels of p53 protein, 1 case presented a nonsense point mutation giving a stop codon. No missense mutations were detected in this group. The finding of p53 mutations in 4 of 16 cases confirms the presence of p53 gene mutations in high grade lymphomas distributed over different histologic groups. These include Burkitt's lymphoma, together with centroblastic, immunoblastic, and large cell lymphoma of mucosa origin. Nevertheless, the absence of mutations in 5 of the 8 cases that overexpressed p53 suggests that the nuclear or cytoplasmic stabilization of p53 protein could also depend on other factors. The absence of detectable levels of p53 protein cannot discount the existence of p53 mutations, as is shown by a case of Burkitt's lymphoma in which a nonsense mutation was detected. The impact of this range of p53 alterations on clinical course and treatment response of the patients deserves to be explored, in an attempt to differentiate the specific consequences of each one.

scholarly journals Mutations of the p53 gene in lymphoid leukemia

Blood ◽  
1991 ◽  
Vol 77 (6) ◽  
pp. 1153-1156 ◽  
Author(s):  
K Sugimoto ◽  
H Toyoshima ◽  
R Sakai ◽  
K Miyagawa ◽  
K Hagiwara ◽  
...  
Keyword(s):  
Lymphoblastic Leukemia ◽  
Gene Mutations ◽  
P53 Gene ◽  
Single Strand Conformation Polymorphism ◽  
Suppressor Gene ◽  
Nucleotide Sequencing ◽  
Polymorphism Analysis ◽  
Coding Region ◽  
Lymphoid Leukemia ◽  
Nucleotide Insertion

Abstract p53 is currently considered to be a tumor suppressor gene product, and its alterations are suggested to be involved in several human malignancies. Here we show evidence of the possible involvement of p53 gene mutations in lymphoid leukemias studied by reverse transcriptase- polymerase chain reaction, single strand conformation polymorphism analysis, and nucleotide sequencing. Fourteen patients with various leukemias were examined and two with acute lymphoblastic leukemia and one with Waldenstrom's macroglobulinemia were identified to have mutations in the coding region of the p53 gene. These mutations included point mutation, triplet deletion, and single nucleotide insertion. Furthermore, expression of the wild-type p53 mRNA was not detected in the samples from these three patients. In one of them, chromosome 17p was deleted, suggesting the absence of the nonmutated p53 gene, whereas in the other two patients, chromosome 17p seemed to be intact by cytogenetic analysis. Our results suggest that alterations of the p53 gene may have a role in the genesis of some leukemias.

scholarly journals Mutations of the p53 gene in myelodysplastic syndrome (MDS) and MDS- derived leukemia

Blood ◽  
1993 ◽  
Vol 81 (11) ◽  
pp. 3022-3026 ◽  
Author(s):  
K Sugimoto ◽  
N Hirano ◽  
H Toyoshima ◽  
S Chiba ◽  
H Mano ◽  
...  
Keyword(s):  
Myelodysplastic Syndrome ◽  
Point Mutations ◽  
Gene Mutations ◽  
P53 Gene ◽  
Single Strand Conformation Polymorphism ◽  
Nucleotide Sequencing ◽  
Polymorphism Analysis ◽  
P53 Gene Mutation ◽  
Ras Gene ◽  
P53 Gene Mutations

The p53 gene is currently thought to be a tumor suppressor gene, and its alterations have been suggested to be involved in the pathogenesis of several human malignancies, including some leukemias and lymphomas. We present here evidence for the possible involvement of p53 gene mutations in the myelodysplastic syndrome (MDS), although the incidence is relatively low. Forty-four patients with MDS and six patients with overt leukemias that developed from MDS were studied for p53 gene alterations using reverse transcriptase-polymerase chain reaction, single-strand conformation polymorphism analysis, and nucleotide sequencing. Three patients with MDS (2 RAEB and 1 RAEB in T) had missense point mutations in the conserved regions of the p53 coding sequence. Furthermore, expression of the wild-type p53 mRNA was not detected in these three patients. The probable absence of normal p53 function in the three cases studied here suggests that alterations in the p53 gene may occasionally play a role in MDS. These three MDS patients with p53 gene mutations and an MDS-derived erythroleukemia cell line that we had previously reported to carry a p53 gene mutation showed no N-ras gene mutations, suggesting heterogeneity in the oncogenic mechanism of MDS.

scholarly journals p53 mutation is associated with progression in follicular lymphomas

Blood ◽  
1993 ◽  
Vol 82 (7) ◽  
pp. 1994-2004 ◽  
Author(s):  
CA Sander ◽  
T Yano ◽  
HM Clark ◽  
C Harris ◽  
DL Longo ◽  
...  
Keyword(s):  
Complete Remission ◽  
Follicular Lymphoma ◽  
Molecular Mechanisms ◽  
Single Strand Conformation Polymorphism ◽  
Suppressor Gene ◽  
Neoplastic Cell ◽  
P53 Mutation ◽  
Polymorphism Analysis ◽  
Low Grade ◽  
Follicular Lymphomas

The majority of low-grade follicular lymphomas will eventually transform to an aggressive intermediate, or high-grade lymphoma. The molecular mechanisms responsible for this transformation have not been determined. We studied serial biopsies from 34 patients with follicular lymphomas that underwent histologic transformation, for abnormalities of the p53 tumor suppressor gene by a combination of immunohistochemistry, single strand conformation polymorphism analysis (SSCP), and sequencing. We found overexpression of p53 in 10 of the 34 transformed aggressive lymphomas, 9 of which contained mutations identified by SSCP analysis and subsequent sequencing. Matched pretransformation low-grade follicular lymphoma biopsies were available for 7 of the 10 cases. None of six studied by immunohistochemistry showed overexpression of p53 and only 1 of 4 studied by SSCP/sequencing showed the presence of mutation in the pretransformation biopsy. Interestingly, an eighth p53 positive transformed lymphoma recurred with a clonally related, p53 negative low-grade lymphoma 5 years after the patient had achieved a complete remission. Immunohistochemistry also showed that several pretransformation biopsies from p53 positive transformed cases showed rare p53 positive cells and in one case we could document an increase in their number over time. Twenty-five additional low-grade follicular lymphoma biopsies were also examined. Three patients had lymphomas positive for p53 mutation. One of the three subsequently transformed within a year of the biopsy studied; the second patient had an earlier (unavailable) biopsy at a different site that showed transformed histology. The third patient was treated with ProMACE-MOPP combination chemotherapy and attained a complete remission. We conclude that (1) mutations of p53 are associated with histologic transformation in approximately 25% to 30% of follicular lymphomas and (2) p53 positive cells can be detected before histologic transformation, but do not comprise a significant percentage of the neoplastic cell population (identifiable by SSCP) until late in the disease, just before or after histologic progression. Finally, the data also suggest that p53 positive low-grade lymphomas are at risk for progression and that in this subset, aggressive therapy may be warranted.

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